Process for preparing 5-hydroxybenzo [b] thiophene-3-carboxylic acid derivatives

ABSTRACT

Benzothiophenecarboxylic acid derivatives of the formula (I) which are useful as starting materials for producing drugs, and a process for preparing 5-hydroxybenzo[b]-thiophene-3-carboxylic acid derivatives of the formula (VI) which are specific PGD 2  antagonists.

TECHNICAL FIELD

[0001] The present invention relates to5-hydroxybenzo[b]thiophene-3-carboxylic acid derivatives which are keystarting materials for producing compounds useful in the field ofpharmaceuticals.

BACKGROUND ART

[0002] 5-Hydroxybenzo[b]thiophene-3-carboxylic acid derivatives of thegeneral formula (I):

[0003] wherein R is hydrogen or a hydroxy-protecting group are importantstarting materials in the synthesis of pharmacologically activecompounds. For example, a compound of the formula (I) is essential inthe synthesis of benzothiophenecarboxamide derivatives of the generalformula (VI):

[0004] wherein R is as defined above and X is hydrogen or alkyl. Thebenzothiophenecarboxamide derivatives are specific antagonists of PGD₂and known to be useful as a drug in the treatment of various diseasesrelated to mast cell dysfunction caused by excessive production of PGD₂,for example, systemic mastocytosis, disorder of systemic mast cellactivation, tracheal contraction, asthma, allergic rhinitis, allergicconjunctivitis, urticaria, injury due to ischemic reperfusion,inflammation, and atopic dermatis (WO97/00853, PCT/JP97/04527(WO98/25919)). Among compounds of the formula (VI), a compound whereinOR is 5-hydroxy and X is hydrogen (hereinafter, referred to as “CompoundA”) has especially high antagonistic effect on PGD₂, showing anexcellent anti-nasal occlusion activity, and is contemplated to be apromising drug for treating nasal occlusion.

DISCLOSURE OF THE INVENTION

[0005] A process for preparing the above-mentioned compound isillustrated by the following reaction scheme (WO98/25919):

[0006] In order to clinically apply Compound A widely, it is essentialto establish a process for preparing a starting material, the compound(I), which process is safe, efficient and industrially applicable.

[0007] However, it is difficult to synthesize benzothiophene derivativeshaving 5-hydroxyl group like the compound (I) and there have been nomethods industrially applicable so far. The existing methods involvevarious complicated processes and are inefficient and of low yield. Forexample, there have been methods wherein 5-acetoxybenzo[b]thiophene isbrominated to yield 3-bromo-5-acetoxybenzo[b]thiophene, which in turn isre-protected at the 5-acetoxy group with a benzyl group to yield3-bromo-5-benzyloxybenzo[b]thiophene, which is followed by metallizationwith magnesium, introduction of carbon dioxide and removal of the benzylgroup (J. Chem. Soc. (C). 1967, 1899-1905); or 5-bromobenzo[b]-thiopheneis subjected to Friedel-Crafts reaction to yield3-acetyl-5-bromobenzo[b]thiophene, which is followed by oxidation withsodium hypochlorite to yield 5-bromobenzo[b]thiophene-3-carboxylic acid(Nippon-Kagaku Zasshi vol. 86, No. 10, 1067-1072(1965), J. Chem. Soc.(C). 1967, 2084-2089). 5-Hydroxybenzo[b]thiophene-3-carboxylic acid or5-acetoxybenzo[b]thiophene-3-carboxylic acid are then synthesizedstarting from the reaction products above. However, the startingmaterial such as 5-hydroxybenzo[b]-thiophene or 5-bromobenzo[b]thiopheneis not commercially available and had to be synthesized from anappropriate reagent (e.g., J. Am. Chem. Soc., 57, 1611(1935), J.Heterocyclic Chem., 25, 1271(1988)) in all cases, which have made thesynthetic process longer and complex.

[0008] The present invention solves the problems of the existing methodsand provides a method for the preparation of the compounds of theformula (I), which method is industrially applicable, efficient andsafe.

[0009] Thus, the present invention provides a process for preparing acompound of the formula (I):

[0010] wherein R is hydrogen or a hydroxy-protecting group, or areactive derivative thereof comprising subjecting 4-mercaptophenol toreactions for introduction of a propargyl group and protection ofhydroxyl group to yield a compound of the formula (II):

[0011] wherein R¹ is a hydroxy-protecting group; oxidizing the compound(II) to yield a compound of the formula (III):

[0012] wherein R¹ is a hydroxy-protecting group; subjecting the compound(III) to thermal rearrangement reaction to yield a compound of theformula (IV):

[0013] wherein R¹ is as defined above; and subjecting the compound (IV)to stepwise oxidation of hydroxymethyl group and optionallydeprotection.

[0014] The present invention also provides a process for preparing acompound of the formula (I):

[0015] wherein R is hydrogen or a hydroxy-protecting group or a reactivederivative thereof comprising subjecting 5-hydroxybenzo[b]thiophene to aprotecting reaction to yield a compound of the formula (VII):

[0016] wherein R² is a hydroxy-protecting group; reacting the compound(VII) with acetyl halide under the conditions for Friedel-Craftsreaction to yield a compound of the formula (VIII):

[0017] wherein R² is a hydroxy-protecting group; and subjecting thecompound (VIII) to oxidation of the acetyl group and optionallydeprotection.

[0018] The present invention further provides a method for thepreparation of the above-mentioned5-hydroxybenzo[b]-thiophene-3-carboxylic acid derivative of the generalformula (VI) by using a compound of the formula (I). Thus, the presentinvention provides a process for preparing a compound of the formula(VI):

[0019] wherein R is as defined above and X is hydrogen or alkyl, anddouble bond represents either E- or Z-configuration, or apharmaceutically acceptable salt thereof or a hydrate thereof, whichcomprises subjecting a compound of the formula (I) or a reactivederivative thereof to the following reactions:

[0020] (1) reaction with a compound of the formula (V)

[0021] wherein X is hydrogen or alkyl; or

[0022] (2) reaction with a compound of the formula (V′):

[0023] or a salt thereof followed by oxidation and reaction with anylide under the conditions for Wittig reaction; and

[0024] (3) optionally deprotection.

THE BEST EMBODIMENT FOR PRACTICING THE INVENTION

[0025] The terms used herein are defined below.

[0026] The term “hydroxy-protecting group” means alkyl, alkoxyalkyl,acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl,alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl ortetrahydropyranyl.

[0027] The term “alkyl” means C₁-C₂₀ linear or branched alkyl,particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl,hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl,tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl,icosyl and the like, and C₁-C₆ alkyl is preferred.

[0028] The term “alkoxy” means C₁-C₆ linear or branched alkoxy,particularly, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy,s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy,t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxyand the like, and C₁-C₃ alkoxy is preferred.

[0029] The term “alkoxyalkyl” means alkyl group substituted by alkoxygroup, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl,ethoxyethyl, methoxypropyl and the like.

[0030] The term “acyl” means C₁-C₁₁ acyl derived from aliphaticcarboxylic acid or aromatic carboxylic acid. Examples of aliphaticcarboxylic acid-derived acyl include acetyl, chloroacetyl,trichloroacetyl, propionyl, butyryl, valeryl and the like, and examplesof aromatic carboxylic acid-derived acyl include benzoyl,p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl andthe like.

[0031] The term “aryl” means phenyl, naphthyl or polycyclic aromatichydrocarbon group and the like. In addition, aryl may be substituted bythe following substituents.

[0032] Examples of substituent include alkyl such as methyl, ethyl,n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, neopentyl or tert-pentyl, lower alkoxy such as methoxy orethoxy, halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy,carboxy, cyano, sulfonyl, amino, lower alkylamino such as methylamino,dimethylamino, ethylmethylamino or diethylamino, and the like. The arylgroup may have one or more substituents at any possible positions.Specific examples of aryl include 2-methylphenyl, 3-methylphenyl,4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl,4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl,4-(N,N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl,4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and thelike.

[0033] The aryl group in the “aralkyl”, “arylsulfonyl”,“aryloxycarbonyl” or “aralkyloxycarbonyl” described below may havesimilar substituents as defined above.

[0034] The term “aralkyl” means an alkyl group substituted by arylgroup, and includes benzyl, 4-methylbenzyl, 4-methoxybenzyl,3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like.

[0035] The term “alkylsulfonyl” means a sulfonyl group substituted byalkyl group, and includes methanesulfonyl, ethanesulfonyl and the like.

[0036] The term “arylsulfonyl” means a sulfonyl group substituted byaryl group, and includes benzenesulfonyl, p-toluenesulfonyl, and thelike.

[0037] The term “alkyl-substituted silyl” means mono-, di- ortri-alkyl-substituted silyl, for example, methylsilyl, dimethylsilyl,trimethylsilyl, t-butyldimethylsilyl, and the like.

[0038] The term “alkoxycarbonyl” means methoxycarbonyl,isopropoxycarbonyl, t-butoxycarbonyl, and the like.

[0039] The term “aryloxycarbonyl” means phenoxycarbonyl, and the like.

[0040] The term “aralkyloxycarbonyl” means benzyloxycarbonyl, and thelike.

[0041] Although all the above-mentioned hydroxy-protecting groups arepreferred as the hydroxy-protecting group shown by R¹, R² or R inrespective formula above, aryl sulfonyl is more preferred andbenzenesulfonyl is particularly preferred among them.

[0042] Examples of salts of the compound of the general formula (VI)include alkali metal salts such as lithium salt, sodium salt orpotassium salt and the like, alkali earth metal salts such as calciumsalt and the like, ammonium salt, salts with organic base such astromethamine, trimethylamine, triethylamine, 2-aminobutane,tert-butylamine, diisopropylethylamine, n-butylmethylamine,n-butyldimethylamine, tri-n-butylamine, cyclohexylamine,dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine,benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine,2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine,diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene,2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine,or amino acid salts such as lysine salt or arginine salt.

[0043] The salts of the amino alcohol of the formula (V′) include saltswith organic acid such as benzoic acid, etc., and mineral acid such ashydrochloric acid, sulfuric acid, etc.

[0044] The final compound of the present invention is represented by theformula (VI) as described above, in which the double bond of thealkenylene side chain (5-heptenylene chain) may be in the E- orZ-configuration.

[0045] The method of the present invention is described below in moredetail. When a substituent(s) possibly interfering the reaction ispresent, it can be appropriately protected and then deprotected at adesired stage. Such protection or deprotection can be accomplished by aprocedure known in the art.

[0046] Wherein R and R¹ are as defined above.

[0047] [Step 1]

[0048] This step is related to the introduction of a propargyl group atthe mercapto group of 4-mercaptophenol (1) and protection of hydroxylgroup.

[0049] The introduction of a propargyl group is accomplished by usingpropargyl halide such as propargyl bromide, propargyl chloride and thelike in the presence of a basic agents. The reaction can be accomplishedwithin several tens minutes to several hours at room temperature byemploying, as a basic agent, inorganic base such as potassium carbonate,sodium carbonate or the like, or an organic base such as triethylamine,pyridine, 4-dimethylaminopyridine or the like in a solvent suchas-acetone, ethyl acetate, tetrahydrofuran, acetonitrile, or the like.

[0050] When a strong base such as potassium hydroxide or sodiumhydroxide is used, it can be also accomplished in a two-layer solventsystem such as toluene-water or xylene-water.

[0051] The protection of hydroxyl group may be conducted using anordinary hydroxy-protecting group in a conventional manner. Preferredprotecting groups to be used in the present method are those which donot undergo changes during the oxidative reactions in the 2nd and 4thsteps of the present Process and the 2nd step of Process IV below forthe preparation of compound of the formula (VI) and also during theWittig reaction of the 3rd step of said Process, and can be easilydeprotected in the 4th step to give leaving groups which are easilyseparable from, for example, Compound A for purification thereof, whichcorresponds to a compound of the formula (VI) wherein OR is 5-hydroxy, Xis hydrogen and double bond is in Z-configuration. Examples of such ahydroxy-protecting group include alkyl, alkoxyalkyl, acyl, aralkyl,alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl,aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.

[0052] Considering the requirements that a protecting group shouldsurvive during the Wittig reaction conducted under strong basicconditions, be easily deprotected, for example, in the 4th step for thepreparation of Compound A, and be separable from Compound A,arylsulfonyl is more preferred and benzenesulfonyl is particularlypreferred. Benzenesulfonyl group is relatively stable to base inanhydrous solvents and, upon deprotection, gives benzenesulfonic acidwhich is water-soluble and is easily separated from the final product ofthe formula (VI). The protection and deprotection can be carried out bya method known in the art. For example, in the case of benzenesulfonylgroup, the introduction of benzenesulfonyl group is carried out in amanner similar to that for the introduction of propargyl group by usingbenzenesulfonyl chloride.

[0053] [Step 2]

[0054] This step is related to oxidation of the compound (II). Therehave been known oxidizing methods which use, for instance, aqueoushydrogen peroxide - acetic acid (J. Am, Chem. Soc., 87, 1109-1114(1965)),aqueous hydrogen peroxide-titanium(III) chloride (Synthesis1981, 204-206), m-chloroperbenzoic acid (Org. Synth., 64, 157-163(1985)), or sodium metaperiodate (J. Org. Chem., 27, 282-284 (1962)). Inthe present step, it is preferred to use a slightly excess amount of 30%aqueous hydrogen peroxide in an alcoholic solvent such as ethanol,methanol, isopropanol or tert-butanol solution containing formic acid.The reaction is accomplished within several tens minutes to severalhours under cooling or at room temperature.

[0055] [Step 3]

[0056] This step is related to the conversion of the compound (III) intothe hydroxymethyl compound (IV) by thermal rearrangement reaction. Thethermal rearrangement reaction in this step is carried out according tothe method described in J. C, S. Chem. Comm., 1974, 848-849. Examples ofpreferred solvents for this reaction include dioxane,1,2-dimethoxyethane, propyl acetate and 3-pentanone. The reaction isaccomplished by refluxing in a solvent for several hours followed byadding to the resultant intermediate an acid (p-toluenesulfonic acid,methanesulfonic acid, sulfuric acid, etc.)

[0057] [Step 4]

[0058] This step is related to the oxidation of the compound (IV) toprovide carboxylic acid (I). The oxidation can be carried out eitherdirectly or in a stepwise manner. Examples of oxidizing agent forconverting an aromatic primary alcohol to the corresponding carboxylicacid directly include chromic acids (Synthesis. 1986, 285-288),potassium permanganate (J. Org. Chem., 18, 806-809 (1953)) and rutheniumoxides (J. C. S. Chem. Comm., 1979, 58-59)). However, these methods havedisadvantages in not only the yield but also the following matters. Forinstance, the reaction time is long, the detoxification treatment ofoxidizing agent is needed following the reaction, the reagents areunstable and/or they involve complicated operations.

[0059] On the contrary, in some cases, a stepwise oxidation wherein aprimary alcohol is oxidized to an aldehyde and then to a carboxylic acidmay be of advantage with regard to yield. In general, the oxidation ofalcohol to aldehyde has been carried out by using an oxidizing agent ofchromic acid series, for example, Jones reagents (J. Org. Chem., 40,1664-1665 (1975)), Collins reagents (J. C. S. Chem. Comm., 1972 1126)),pyridinium chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). It hasbeen also known a method which uses manganese dioxide (Helv. Chim.Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J.Org. Chem., 43, 2480-2482 (1978)). However, these existing methods havedisadvantages. For example, chromic acids are toxic to human body andmust be detoxified after use. Further, the Swern oxidation usingdimethyl sulfoxide-oxalyl chloride is not suited for a large scaleproduction because it is accompanied by the generation of carbonmonoxide harmful to workers and sulfurous odor and also it must becarried out at low temperature, for example, between −50° C. and −78° C.

[0060] Alcohol (IV) can be converted into aldehyde (IV′) almostquantitatively by a method wherein an alcohol (IV) is oxidized with anoxidizing reagent such as halo oxoacid in the presence of2,2,6,6-tetramethylpiperidine-1-oxyl or the like (referred to as“TEMPOs”) according to the description in a literature (e.g., J. Org.Chem., 52, 2559-2562 (1987)), whereby the problems of the existingmethods are solved. Examples of TEMPOs usable include2,2,6,6,-tetramethylpiperidine-1-oxyl,4-methoxy-2,2,6,6,-tetramethylpiperidine-1-oxyl,4-acetylamino-2,2,6,6,-tetramethylpiperidine-1-oxyl,4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and4-cyano-2,2,6,6,-tetramethylpiperidine-1-oxyl. Examples of usable halooxoacids include sodium hypochlorite, sodium hypobromite, sodium bromiteand higher bleaching powder. A solution of an oxidizing agent may beadjusted to, for example, pH 8.5 to 9.5 with a mineral acid such assodium hydrogen carbonate, hydrogen chloride or sulfuric acid.Alternatively, a solution of an oxidizing agent may be added in thepresence of sodium hydrogen carbonate. The reaction can be accomplishedwithin several minutes to several tens minutes at temperature fromice-cooling to room temperature in a solvent such as ethyl acetate,acetonitrile or dichloromethane.

[0061] When the reaction solution containing the resultant aldehyde(IV′) is acidified and sodium chlorite and aqueous hydrogen peroxide areadded thereto, the aldehyde is converted into carboxylic acid underice-cooling within several tens minutes to several hours.

[0062] If desired, the product may be further subjected to thedeprotection of 5-hydroxy-protecting group and/or conversion intoreactive derivatives at 3-carboxyl group. Such “reactive derivative”includes the corresponding acid halides (e.g., chloride, bromide,iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid oracetic acid), activated esters (e.g., succinimide ester), and the like,and includes acylating agents generally used for the acylation of aminogroup. For example, to obtain acid halides, a carboxylic acid is reactedwith thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g.,phosphorous trichloride, phosphorous pentachloride), oxalyl halide(e.g., oxalyl chloride), or the like, according to a known method (e.g.,Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis852-854(1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)).

[0063] wherein R and R² are as defined above.

[0064] [Step 1]

[0065] This step is related to the protection of 5-hydroxy group ofcompound (7).

[0066] The compound (7) as the starting material of the present step isknown in a literature (J. Am. Chem. Soc., 57, 1611-1616 (1935), Ann.Chem., 527, 83-114 (1938), J. Am. Chem. Soc., 78, 5351-5357 (1956), J.Org. Chem., 41, 1118-1124 (1976)). The hydroxyl group of this compoundis protected appropriately in a manner similar to that descried in the1st step of Process I above. For example, when benzenesulfonyl group isused, the compound is added to benzenesulfonyl chloride in the presenceof an inorganic base such as sodium carbonate or potassium carbonate, oran organic base such as triethylamine or tripropylamine. Example ofpreferred solvent includes acetone, ethyl acetate and tetrahydrofuran.The reaction is accomplished within several minutes to several hours attemperature from room temperature to the boiling point of the solvent.The compound (VII) can be also synthesized by a broadly used method,commonly known as “Schotten-Baumann reaction”.

[0067] [Step 2]

[0068] This step is related to the introduction of acetyl group to the3-position of the compound (VII) by Friedel-Crafts reaction. Theintroduction of acetyl group is, for example, carried out using acetylchloride or acetyl bromide in the presence of a catalyst, for example, aLewis acid such as aluminium chloride, ferric chloride, zinc chloride,tin chloride and boron trifluoride. Example of usable solvent includescarbon disulfide, nitrobenzene or a halogenated hydrocarbons such asmethylene chloride or ethylene chloride. The reaction is in generalaccomplished within several hours at temperature of ice-cooling to roomtemperature. The 2-acetyl compound slightly produced as a by-product iseasily separable by recrystallization.

[0069] [Step 3]

[0070] This step is related to the conversion of the compound (VIII)into a carboxylic acid (I) or a reactive derivative thereof through theoxidation of the acetyl group in the presence of a salt of hypohalousacid. Examples of preferred hypohalogenite include alkali metal oralkaline earth metal salts of hypohalous acids, and potassium, sodium orcalcium salt of hypochlorous or hypobromous acid is especiallypreferred.

[0071] In an aqueous solution of such a salt, the oxidation progressesat relatively low temperature. However, dioxane or 1,2-dimethoxyethanemay be used as a solvent so as to increase the solubility of thecompound to be oxidized. The reaction is accomplished within severalhours to several tens hours at room temperature or with heating.

[0072] wherein R and X are as defined above and the double bondrepresents E- or Z-configuration.

[0073] This process is related to the synthesis of a compound of theformula (VI) by reacting a compound of the formula (I) or a reactivederivative thereof obtained in Process I or II above with a compound ofthe formula (V).

[0074] The compound (V) used in the present process is obtainableaccording to the method described in Japanese Patent Publication(KOKOKU) No. 6-23170 (23170/1994).

[0075] The reaction can be carried out under ordinary conditions foracylation of amino group. For example, when a carboxylic acid halide isused, the reaction is carried out according to a method commonly knownas “Schotten-Baumann reaction”. In general, carboxylic acid halide isadded dropwise to an aqueous alkaline solution of amine with stirringand under cooling while removing the generating acid with alkali.Alternatively, when a carboxylic acid is used as a free acid not areactive derivative, the reaction can be conducted conventionally in thepresence of a coupling agent generally used in the coupling reactionbetween an amine and a carboxylic acid such as dicyclohexylcarbodiimide(DCC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide orN,N′-carbonyldiimidazole.

[0076] wherein R and X are as defined above and the double bondrepresents E- or Z-configuration.

[0077] [Step 1]

[0078] This step is related to the preparation of a compound of theformula. (IX) by reacting a compound of the formula (I) or a reactivederivative thereof with a compound of the formula (V′) or its salt in amanner similar to that described in Process III above. The preparationof some of the compounds of the formula (V′) is described in Chem.Pharm. Bull. Vol.37, No. 6 1524-1533 (1989).

[0079] [Step 2]

[0080] This step is related to the preparation of an aldehyde of theformula (X) by oxidizing a compound of the formula (IX). The reactioncan be carried out for several hours under cooling or at roomtemperature using an oxidizing agent selected from chromic acid seriessuch as Jones reagents, Collins reagents, pyridinium chlorochromate,pyridinium dichromate or dimethyl sulfoxide-oxalyl chloride in a solventsuch as chlorinated hydrocarbons (chloroform, dichloromethane, etc.),ethers (ethyl ether, tetrahydrofuran, etc.), acetone or benzene.

[0081] [Step 3]

[0082] This step is related to the formation of a double bond byreacting a compound of the formula (X) with an ylide(Ph₃P═CH(CH₂)₃COOH). The reaction for providing a double bond can becarried out in a conventional manner for Wittig reaction. The ylidesused in the reaction can be synthesized, in the presence of a base, bytreating a phosphonium salt which has been synthesized fromtriphenylphosphine and an alkyl halide having a desired alkyl group tobe condensed, for example, 5-bromopentanoic acid. Examples of a baseinclude dimsyl sodium, dimsyl potassium, sodium hydride, n-butyllithium, potassium t-butoxide and lithium diisopropylamide. The reactionis accomplished within several hours at room temperature in a solventsuch as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane ordimethyl sulfoxide.

[0083] [Step 4]

[0084] In this step, a compound (VI) wherein R is hydroxy-protectinggroup is optionally deprotected to give compound (VI-1). The reactioncan be carried out in a conventional manner using a catalyst such ashydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxideor barium hydroxide, or the like. The reaction is accomplished withinseveral tens minutes to several hours with heating in a solvent such asmethanol-water, ethanol-water, acetone-water, acetonitrile-water, or thelike, preferably dimethyl sulfoxide-water.

[0085] The following Examples are provided to further illustrate thepresent invention in more detail and should not be interpreted in anyway as to limit the scope thereof. The abbreviations used in theExamples have the following meanings:

[0086] Ph: phenyl

[0087] Ac: acetyl

[0088] TEMPO: 2,2,6,6-tetramethylpiperidine-1-oxyl

EXAMPLE 1

[0089] (1) Step 1

[0090] 4-(2-Propyn-1-ylthio)phenyl benzenesulfonate (2)

[0091] 4-Mercaptophenol (1) (37.85 g, 300 mmol) and propargyl bromide(42.82 g, 360 mmol) were dissolved in ethyl acetate (757 ml). To thesolution was added dropwise triethylamine (42.5 g, 420 mmol) over 25minutes with stirring and under ice-cooling. After stirring for another1.5 hours at the same temperature, triethylamine (42.5 g, 420 mmol) wasadded in one portion, and benzenesulfonyl chloride (63.58 g, 360 mmol)was added dropwise over 20 minutes. After keeping 1 hour at the sametemperature, the cooling bath was removed and the mixture was stirredfor 30 minutes at room temperature and partitioned into two layers byadding ice-water (500 ml) and 2N hydrochloric acid (110 ml). The aqueouslayer was extracted with ethyl acetate (200 ml). The combined organiclayer was washed with water, dried over anhydrous magnesium sulfate, andthen the solvent was distilled off under reduced pressure to provide100.04 g of the title compound (2) as oil. Crude yield: 109%.

[0092] IR (CHCl₃); 3306, 3071, 3031, 3019, 3009, 1585, 1486, 1449, 1378cm⁻¹

[0093]¹H NMRδ (CDCl₃), 300 MHz; 2.23 (1H, t, J=2.7 Hz), 3.56 (2H, d,J=2.7 Hz), 6.94 and 7.34 (each 2H, each d, J=8.7 Hz), 7.51-7.56 (2H, m),7.68 (1H, m), 7.82-7.85 (2H, m)

[0094] (2) Step 2

[0095] 4-(2-Propyn-1-ylthio)phenyl benzenesulfonate (3)

[0096] The compound (2) (60.8 g, 183 mmol) prepared in step (1) abovewas dissolved in formic acid (30.4 ml) and methanol (122 ml), and 31%aqueous hydrogen peroxide (26.29 g, 240 mmol) was then added. After 3.5hours, ice-water (240 ml) was added and the mixture was extracted withethyl acetate (2×300 ml). The combined organic layer was washed with 5%aqueous sodium carbonate and water, dried over anhydrous magnesiumsulfate and the solvent was then distilled off under reduced pressure toprovide 65.47 g of the title compound (3) as oil. Crude yield: 117%.

[0097] IR (CHCl₃); 3305, 3066, 3032, 3012, 1586, 1486, 1449, 1382 cm⁻¹

[0098]¹H NMRδ (CDCl₃), 300 MHz; 2.34 (1H, t, J=3.9 Hz), 3.58 and 3.68(each 1H, each dd, J =3.9 and 23.7 Hz), 7.18 and 7.67 (each 2H, each d,J=9.9 Hz), 7.51-7.59 (2H, m), 7. 66 (1H, m), 7.82-7.87 (2H, m)

[0099] (3) Step 3

[0100] 5-Benzenesulfonyloxy-3-hydroxymethylbenzo[b]thiophene (4)

[0101] The compound (3) (65.47 g, 183 mmol) obtained in above (2) wasdissolved in 1,2-dimethoxyethane (1.6L) and the solution was refluxedfor 4 hours. To the solution were added water (64 ml) andp-toluenesulfonic acid monohydrate (19.2 g, 100 mmol) and refluxing wascontinued for 2 hours. The reaction mixture was concentrated underreduced pressure. After water (200 ml) was added to the resulting oil,the mixture was extracted with ethyl acetate (300 ml). The organic layerwas washed with aqueous sodium hydrogen carbonate and water, dried overanhydrous magnesium sulfate and then the solvent was distilled off underreduced pressure to provide 60.18 g of the title compound (4) as oil.Crude yield: 103%.

[0102] IR (CHCl₃); 3609, 3067, 3033, 3013, 2935, 2878, 1589, 1566, 1449,1435, 1376 cm⁻¹

[0103]¹H NMRδ (CDCl₃) 300 MHz; 4.78 (2H, d, J=0.9 Hz), 6.98 (1H, dd,J=2.4 and 8.7 Hz), 7.26 (1H, s), 7.43-7.45 (2H, m), 7.50-7.55 (2H, m),7.66 (1H, m), 7.73 (1H, d, J=8.7 Hz ), 7.83-7.86 (2H, m)

[0104] (4) Step 4

[0105] 5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6)

[0106] The compound (4) (51.26 g, 155 mmol) prepared in above (3) wasdissolved in acetonitrile (1.54L), and TEMPO(2,2,6,6-tetramethylpiperidine-1-oxyl, 250 mg, 0.01 eq.) was addedthereto. To the mixture was added dropwise 0.81 N aqueous sodiumhypochlorite, which had been prepared by diluting 1.63 N aqueous sodiumhypochlorite (150 ml) with water (75 ml), adjusting pH 8.6 with 1 Nsulfuric acid, and adjusting the total volume to 300 ml, over 15minutes, while maintaining the inner temperature between −1° C. and 8°C. After stirring for 25 minutes at this temperature, 1 N aqueous sodiumsulfite (32 ml) was added. Subsequently, 79% sodium chlorite (27.48 g,240 mmol) and 31% aqueous hydrogen peroxide (23.26 g, 212 mmol) wereadded under ice-cooling. The cooling bath was removed and the mixturewas stirred for 2 hours. The reaction was diluted with water (1.5L),adjusted to pH 3 with 1 N hydrochloric acid and the deposited crystalswere filtered, and washed twice with water (200 ml), acetonitrile (50ml) to provide 32.4 g of crude crystals. The crude crystals (32.4 g)were suspended in acetonitrile (224 ml), refluxed for 15 minutes andcooled on ice. The crystals were filtered and washed with acetonitrile(65 ml) to provide 26.79 g of the title compound (6). Yield: 51.7%, mp202-203° C.

[0107] IR (Nujol): 3102, 2925, 2854, 2744, 2640, 2577, 1672, 1599, 1558,1500, 1460, 1451 cm¹

[0108] NMRδ (CDCl₃), 300 MHz; 7.16 (1H, dd, J=2.7 and 9.0 Hz), 7.55-7.61(2H, m), 7.73 (1H, m), 7.81 (1H, d, J=9.0 Hz), 7.90-7.94 (2H, m), 8.16(1H, d, J=2.7 Hz), 8.60 (1H, s)

[0109] Elemental Analyses for C₁₅H₁₀O₅S₂ Calculated (%): C, 53.88; H,3.01; S, 19.18 Found (%): C, 53.73; H, 3.24; S, 19.09

EXAMPLE 2

[0110] (1) Step 1

[0111] 5-Benzenesulfonyloxybenzo[b]thiophene (8)

[0112] The compound (7) [J. Am. Chem. Soc., 57, 1611-1616 (1935) ; Ann.Chem., 52, 83-114 (1938), J. Am. Chem. Soc., 78, 5351-5357 (1956); J.Org. Chem., 41, 1118-1124 (1976)] (1.36 g, 9.05 mmol) and triethylamine(1.89 ml, 13.6 mmol) were dissolved in tetrahydrofuran (10 ml). To thesolution was added dropwise a solution of benzenesulfonyl chloride (1.92g, 10.9 mmol) in tetrahydrofuran (3 ml). After being stirred for 2hours, the reaction mixture was diluted with water and extracted withtoluene. The organic layer was washed with water, dried over anhydrousmagnesium sulfate and then the solvent was distilled off under reducedpressure. The residue was chromatographed over silica gel (5:1 hexane:ethyl acetate) and then recrystallized from hexane containing smallamount of ethyl acetate to provide 2.28 g of the title compound (8).Yield: 86.8%, mp 80-81° C.

[0113] IR (Nujol): 1599, 1579, 1564, 1497, 1448, 1440, 1415, 1352 cm⁻¹

[0114]¹H NMRδ (CDCl₃); 300 MHz; 6.92 (1H, dd, J=2.4 and 8.7 Hz), 7.26(1H, dd, J=0.9 and 5.4 Hz), 7.47 (1H, d, J=2.4 Hz), 7.51 (1H, d, J=5.4Hz), 7.52-7.55 (2H, m), 7.67 (1H, m), 7.74 (1H, d, J=8.7 Hz), 7.83-7.87(2H, m)

[0115] Elemental Analyses for C₁₄H₁₀O₃S₂ Calculated (%): C, 57.91; H,3.47; S, 22.09 Found (%): C, 57.72; H, 3.45; S, 21.98

[0116] (2) Step 2

[0117] 3-Acetyl-5-benzenesulfonyloxy-benzo[b]thiophene (9)

[0118] Powdered aluminum chloride (1.34 g, 10 mmol) was suspended indichloromethane (10 ml). To the suspension was added dropwise acetylchloride (1.02 ml, 14.3 mmol) over 5 minutes with stirring and underice-cooling. Subsequently, a solution of the compound (8) (2.075 g, 7.2mmol) prepared above in dichloromethane (6 ml) was added dropwise over15 minutes. After being stirred for 2 hours at the same temperature andthen for 2.5 hours at room temperature, the solution was poured intoice-water and extracted with dichloromethane. The organic layer waswashed with water, dried over anhydrous magnesium sulfate and then thesolvent was distilled off under reduced pressure. The resulting residuewas recrystallized from ethyl acetate (3 ml) and hexane (3 ml) toprovide 2.01 g of the title compound (9). Yield: 84.4% mp 129-130° C.

[0119] IR (Nujol): 3094, 1672, 1619, 1596, 1556, 1494, 1450, 1437, 1428,1369 cm⁻¹

[0120]¹H NMRδ (CDCl₃); 300 MHz; 2.58 (3H, s), 7.22 (1H, ddd, J=0.6, 2.4and 9.0 Hz), 7.52-7.58 (2H, m), 7.69 (1H, m), 7.79 (1H, d, J=9.0 Hz),7.87-7.91 (2H, m), 8.27 (1H, dd, J=0.6 and 2.4 Hz), 8.31 (1H, s)

[0121] Elemental Analyses for C₁₆H₁₂O₄S₂ Calculated (%): C, 57.82; H,3.64; S, 19.29 Found (%): C, 57.62; H, 3.71; S, 19.23

[0122] (3) Step 3

[0123] 5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6)

[0124] The compound (9) (6.65 g, 20 mmol) prepared in above (2) wasdissolved in dioxane (50 ml), and 10% sodium hypochlorite (46.2 ml) wasadded over 20 minutes with stirring while maintaining the temperature at10-12° C. After 7 hours, the reaction mixture was diluted with ice-water(80 ml) and acidified with conc. hydrochloric acid (5.2 ml). Thedeposited crystals were filtered, washed ,with water, dried to provide5.84 g of crude crystals. The 5.84 g of the crude crystals wererecrystallized from methanol (66 ml) and water (16 ml) to provide 5.51 gof the title compound (6). Yield: 82.4%. mp 203-204° C.

[0125] This compound is identical to the compound (6) prepared inExample 1.

REFERENCE EXAMPLE 1

[0126] 5-Benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (10)

[0127] 5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6)(5.582 g, 16.7 mmol) prepared in Examples above was refluxed for 1.5hours with dimethylformamide (1 drop), thionyl chloride (3.57 ml, 50mmol) and toluene (22 ml), and the solvent was removed under reducedpressure to provide 5.89 g of the title compound (10).

REFERENCE EXAMPLE 2

[0128] (1) Step 1:

[0129] 5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11)

[0130] 5-Benzenesulfonyloxybenzo[b]thiophene-3-carboxylic acid (6) (100mg, 0.3 mmol) prepared in Examples above was dissolved in 1 N sodiumhydroxide (1.2 ml) and heated at 40° C. for 8 hours with stirring. Tothe reaction solution was added 1 N hydrochloric acid (1.2 ml), and thedeposited crystals were filtered, washed with water and dried to provide58 mg of the title compound (11). Yield: 96.6% mp 262-263° C.

[0131] This compound (11) is identical to5-hydroxybenzo[b]thiophene-3-carboxylic acid described in M.Martin-Smith et al. J. Chem. Soc (C) , 1899-1905 (1967).

[0132] (2) Step 2:

[0133] 5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12)

[0134] 5-Hydroxybenzo[b]thiophene-3-carboxylic acid (11) (1,140 mg)prepared in above (1) was dissolved in acetic anhydride (2 ml), pyridine(4 ml). After 3 hours, water was added and the mixture was continuouslystirred under ice-cooling for 1.5 hours. The deposited crystals werefiltered, washed with water and dried to provide 1,349 mg of the titlecompound (12). Yield: 97.3% mp 239-240° C.

[0135]¹H NMRδ (CDCl₃), 300 MHz; 2.37(H, s), 7.20 (1H, dd, J=2.4 and 8.7Hz), 7.87 (1H, d, J=8.7 Hz), 8.34 (1H, d, J=2.4 Hz), 8.57 (1H, s)

[0136] (3) Step 3

[0137] 5-Acetoxybenzo b]thiophene-3-carbonyl chloride (13)

[0138] 5-Acetoxybenzo[b]thiophene-3-carboxylic acid (12) (1,349 mg)prepared above was refluxed for 1.5 hours with dimethylformamide (1drop), thionyl chloride (1.22 ml) and toluene (25 ml). The solvent wasremoved under reduced pressure to provide 1,454 mg of the title compound(13).

EXAMPLE 3

[0139](5Z)-7-[(1R,2R,3S,5S)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (17)

[0140] (1) Step 1: Preparation of[3-[(1R,2R,3R,5S)-3-(2-Hydroxyethyl)-10-norpinan-2-yl]carbamoylbenzo[b]thiophen-5-yl]benzenesulfonate (14)

[0141] Benzoic acid salt of(+)-2-[(1R,2R,3R,5S)-2-Amino-10-norpinan-3-yl]ethanol (described inChem. Pharm. Bull. Vol.37, No. 6 1524-1533(1989) (V′-1)) (5.1 g, 16.7mmol) was suspended in water (10 ml). To the suspension was added 1 Nhydrochloric acid (17 ml) and deposited benzoic acid was removed byextracting with ethyl acetate. The organic layer was washed with water(10 ml). To the combined aqueous layer was added 4 N sodium hydroxide(9.2 ml, 36.8 mmol) under ice-cooling. A solution of5-benzenesulfonyloxybenzo[b]thiophene-3-carbonyl chloride (10) (5.89 g,16.7 mmol) in tetrahydrofuran (36 ml) was then added dropwise over 15minutes with stirring. After stirring for 1 hour at the sametemperature, 1 N hydrochloric acid (4 ml) was added and the mixture wasextracted with ethyl acetate. The organic layer was washed with water,dried over anhydrous magnesium sulfate and then the solvent wasdistilled off under reduced pressure to provide 8.00 g (95.6%) of thetitle compound (14) as colorless amorphous.

[0142]¹H NMRδ (CDCl₃), 300 MHz; 0.96 (1H, d, J=9.9 Hz), 1.12 and 1.26(each 3H, each s), 1.50-2.42(9H, m), 3.69-3.82 (2H, m), 4.30 (1H, m),6.21 (1H, d, J=8.1 Hz), 7.06 (1H, dd, J=2.4 and 8.7 Hz), 7.51-7.56 (2H,m), 7.67 (1H, m), 7.73 (1H, d, J=8.7 Hz), 7.85 -7.88 (2H, m), 7.88 (1H,s), 8.06 (1H, d, J=2.4 Hz).

[0143] [a]_(D) ²⁵+35.70° (c=1.00%, CH₃OH)

[0144] (2) Step 2: Preparation of[3-[(1R,2R,3R,5S)-3-Formylmethyl-10-norpinan-2-yl]carbamoylbenzo[b]thiophen-5-yl]benzenesulfonate (15)

[0145] To dimethyl sulfoxide (3.16 ml, 44.5 mmol) dissolved indimethoxyethane (50 ml) was added oxalyl chloride (1.91 ml, 21.9 mmol)under cooling at −60°60 C.-−65° C. A solution of compound (14) (7.352 g,14.7 mmol) in 1,2-dimethoxyethane (58 ml) was added dropwise at the sametemperature. After stirring the mixture at −55° C.-−60° C. for 30minutes, triethylamine (6.1 ml) was added and, 30 minutes later, thecooling bath was removed to allow the mixture to warm up to roomtemperature. The reaction mixture was diluted with water (100 ml) andextracted with toluene. The organic layer was washed with water, driedover anhydrous magnesium sulfate and then the solvent was distilled offunder reduced pressure. The resulting residue was purified bychromatography on silica gel (hexane: ethyl acetate=5:5−4:6) to provide7.32 g (100%) of the title compound (15) as colorless amorphous.

[0146] IR (CHCl₃); 3443, 3093, 3066, 3030, 3016, 2925, 2871, 2828, 2729,1720, 1655, 1599, 1558, 1513, 1377 cm⁻¹

[0147]¹H NMRδ (CDCl₃), 300 MHz; 0.97 (1H, d, J=10.2 Hz), 1.17 and1.28(each 3H, each s), 1.46 (1H, m), 2.03 (1H, m), 2.22 (1H, m),2.36-2.60(3H, m), 2.69 (1H, ddd, J=1.2, 8.7 and 17.4 Hz), 3.14 (1H, dd,J=4.5 and 17.4 Hz), 4.28 (1H, m), 6.18 (1H, d, J=8.1 Hz), 7.09 (1H, dd,J=2.4 and 8.7 Hz), 7.50-7.55 (2H, m), 7.67 (1H, m), 7.75 (1H, d, J=8.7Hz), 7.85-7.89 (2H, m), 7.89 (1H ,s), 8.03 (1H, d, J=2.4 Hz), 9.80 (1H,d, J=1.2 Hz)

[0148] [a]_(D) ²³+31.8° (c=1.00%, CH₃OH)

[0149] (3) Step 3: Preparation of (5Z)-7-[(1R,2R,3S,5S)-2-(5-Benzenesulfonyloxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (16)

[0150] 4-Carboxybutyltriphenylphosphonium bromide (12.17 g, 27.5 mmol)and potassium t-butoxide (7.19 g, 64.1 mmol) were suspended intetrahydrofuran (64 ml) and stirred for 1 hour under ice-cooling. To thereaction mixture was added over 15 minutes a solution of the compound(15) (9.11 g, 18.3 mmol) prepared in above (2) in tetrahydrofuran (27ml) and the mixture was continuously stirred for 2 hours at the sametemperature. The reaction mixture was diluted with water (80 ml) andwashed with toluene (2×105 ml). After adjusting the aqueous layer to pH8.1 with 5 N hydrochloric acid (4.8 ml), anhydrous calcium chloride (8.1g, 73 mmol) dissolved in water (16 ml) was added, and the mixture wasextracted with ethyl acetate (2×100 ml). Water (100 ml) was added to theorganic layer, and the aqueous layer was adjusted to below pH 2 with 5 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate and thenthe solvent was distilled off under reduced pressure to provide 11.06 gof the compound (16). The compound (16) was used in the next reactionwithout further purification.

[0151] (4) Step 4: Preparation of(5Z)-7-[(1R,2R,3S,5S)-2-(5-Hydroxybenzo[b]thiophen-3-ylcarbonylamino)-10-norpinan-3-yl]-5-heptenoicacid (17) (Compound A))

[0152] The compound (16) (11.06 g, 18.3 mmol) prepared in above (3) wasdissolved in dimethyl sulfoxide (22 ml). After adding 4 N sodiumhydroxide (27.5 ml), the mixture was heated at 55° C. for 2 hours withstirring. The reaction mixture was diluted with water (130 ml) andwashed with toluene (2×65 ml). The aqueous layer was acidified with 5 Nhydrochloric acid and extracted with ethyl acetate. The organic layerwas washed with water, dried over anhydrous magnesium sulfate, and thesolvent was distilled off under reduced pressure to provide 8.26 g ofthe crude objective compound which was then dissolved in methanol (40ml) and water (16 ml). The solution was seeded and gradually cooled withstirring. The deposited crystals were filtered and washed with water:methanol (2:5) to provide 6.35 g of the objective compound. Yield:78.6%. The crystals were dissolved in methanol (40 ml). To the solutionwas added water (12 ml) over 7 minutes with stirring. The mixture wasseeded and continuously stirred for 1 hour at 25° C. After adding water(7 ml) over 40 minutes, the mixture was stirred for 1.5 hours at 25° C.The deposited crystals were filtered and washed with water: methanol(3:5) (8 ml) to provide 6.14 g of the objective compound (17) which wasalmost colorless. Yield: 76.0%, mp 145-146° C.

[0153] IR (Nujol); 3313, 3096, 3059, 3001, 1717, 1627, 1603, 1548, 1469,1440 cm⁻¹

[0154]¹H NMRδ (CDCl₃), 300 MHz; 1.02 (1H, d, J=10.2 Hz), 1.12 and 1.24(each 3H, each s), 1.56-2.55(14H, m), 4.29 (1H, m), 5.32-5.51 (2H, m),6.20 (1H, d, J=9.3 Hz), 7.01 (1H, dd, J=2.4 and 9.0 Hz), 7.66 (1H, d,J=9.0 Hz), 7.69 (1H ,s), 8.03 (1H, d, J=2.4 Hz)

[0155] [a]_(D) ^(24+50.7)° (c=1.01, CH₃OH)

[0156] Elemental Analyses for C₂₅H₃₁NO₄S Calculated (%): C, 68.00; H,7.08; N, 3.17; S, 7.26 Found (%): C, 67.84; H, 7.08; N, 3.24; S, 7.31

1. A process for preparing a compound of the formula (I):

wherein R is hydrogen or a hydroxy-protecting group, or a reactivederivative thereof, which comprises subjecting 4-mercaptophenol toreactions for introduction of a propargyl group and protection ofhydroxyl group to yield a compound of the formula (II):

wherein R¹ is a hydroxy-protecting group; oxidizing the compound (II) toyield a compound of the formula (III):

wherein R¹ is a hydroxy-protecting group; subjecting the compound (III)to thermal rearrangement reaction to yield a compound of the formula(IV):

wherein R¹ is as defined above; and subjecting the compound (IV) tostepwise oxidation of hydroxymethyl group and optionally deprotection.2. The process of claim 1, wherein the hydroxy-protecting grouprepresented by R¹ is alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl,arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl,aralkyloxycarbonyl or tetrahydropyranyl.
 3. The process of claim 1,wherein the hydroxy-protecting group represented by R¹ is arylsulfonyl.4. A process for preparing a compound of the formula (VI):

wherein R is as defined above and X is hydrogen or alkyl, and doublebond represents either E- or Z-configuration, or a pharmaceuticallyacceptable salt or hydrate thereof, which comprises subjecting acompound of the formula (I) or a reactive derivative thereof obtainedaccording to the method of claim 1 to the following reactions: (1)reaction with a compound of the formula (V)

wherein X is hydrogen or alkyl; or (2) reaction with a compound of theformula (V′):

or a salt thereof followed by oxidation and reaction with an ylide underthe conditions for Wittig reaction; and (3) optionally deprotection. 5.A process for preparing a compound of the formula (I):

wherein R is hydrogen or a hydroxy-protecting group, or a reactivederivative thereof, which comprises subjecting5-hydroxybenzo[b]thiophene to protecting reaction to yield a compound ofthe formula (VII):

wherein R² is a hydroxy-protecting group; reacting the compound (VII)with acetyl halide under the conditions for Friedel-Crafts reaction toyield a compound of the formula (VIII):

wherein R² is a hydroxy-protecting group; subjecting the compound (VIII)to oxidation of acetyl group and optionally deprotection.
 6. The processof claim 5, wherein the hydroxy-protecting group represented by R² isalkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl,alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl,aralkyloxycarbonyl or tetrahydropyranyl.
 7. The process of claim 5,wherein the hydroxy-protecting group represented by R² is arylsulfonyl.8. A process for preparing a compound of the formula (VI):

wherein R and X are as defined above, and double bond represents E- orZ-configuration, or a pharmaceutically acceptable salt or hydratethereof, which comprises subjecting a compound of the formula (I):

wherein R is as defined above or a reactive derivative thereof obtainedaccording to the method of claim 5 to the following reactions: (1)reaction with a compound of the formula (V)

wherein X is as defined above; or (2) reaction with a compound of theformula (V′):

or a salt thereof followed by oxidation and reaction with an ylideunder-the conditions for Wittig reaction; and (3) optionallydeprotection.
 9. A compound of the formula (I) wherein R is arylsulfonylor a reactive derivative thereof.
 10. A compound of the formula (I)wherein R is benzenesulfonyl or a reactive derivative thereof.